Dynamics of haem oxygenase-1 expression and bilirubin production in cellular protection against oxidative stress

Abstract

The inducible isoform of haem oxygenase (HO-1) has been proposed as an effective system to counteract oxidant-induced cell injury. In several circumstances, this cytoprotective effect has been attributed to increased generation of the antioxidant bilirubin during haem degradation by HO-1. However, a direct implication for HO-1-derived bilirubin in protection against oxidative stress remains to be established. In the present study, we examined the dynamics of HO-1 expression and bilirubin production after stimulation of vascular smooth-muscle cells with hemin, a potent inducer of the HO-1 gene. We found that hemin-mediated increase in HO-1 protein expression and haem oxygenase activity is associated with augmented bilirubin levels. The majority of bilirubin production occurred early after exposure of cells to hemin. Hemin pre-treatment also resulted in high resistance to cell injury caused by an oxidant-generating system. Interestingly, this protective effect was manifest only when cells were actively producing bilirubin as a consequence of increased haem availability and utilization by HO-1. Tin protoporphyrin IX, an inhibitor of haem oxygenase activity, significantly reduced bilirubin generation and reversed cellular protection afforded by hemin treatment. Furthermore, addition of bilirubin to the culture medium markedly reduced the cytotoxicity produced by oxidants. Our findings provide direct evidence that bilirubin generated after up-regulation of the HO-1 pathway is cytoprotective against oxidative stress.

Heme Regulation in Traumatic Brain Injury: Relevance to the Adult and Developing Brain

“…The beneficial effect of HO-1 is in general agreement with many prior observations in neural and nonneural systems (Chen et al, 2003;Clark et al, 2000;Turner et al, 1999).…”

Cluster analysis of rat pancreatic islet gene mRNA levels after culture in low-, intermediate- and high-glucose concentrations

“…Together with other genes displaying a similar mRNA profile, these genes may play a role in the pro-apoptotic effect of prolonged culture in G2 and G5 instead of in G10 [12][13][14]26]. Finally, among genes with a V-shaped profile, Mt1a and Hmox1 are considered good markers of beta cell oxidative stress and seem to confer protection against beta cell apoptosis under stressful conditions [29,30]. Other genes with a similar mRNA profile such as Myc and Casp4 may, in contrast, play a role in activation of beta cell apoptosis by oxidative stress.…”

Heme-oxygenase-1-induced protection against hypoxia/reoxygenation is dependent on biliverdin reductase and its interaction with PI3K/Akt pathway

“…The cytoprotective properties of HO-1 have traditionally been attributed to the by-products of heme degradation, namely bilirubin and carbon monoxide (CO). Indeed, within a narrow therapeutic range, these catalytic by-products exert powerful antioxidant [15,31], antiinflammatory [32] and anti-apoptotic effects [33][34][35], leading to reduced infarct size [16,17,[36][37]. However, emerging evidence, suggests that HO-1 may also exert cytoprotective effects, independent of heme breakdown [38] by interacting with survival signaling pathways such as PI3K-Akt and p38.…”

“…Another mechanism by which HO-1 may protect cells or tissues against oxidative injury is by generating bilirubin from catabolism of heme. Several studies have demonstrated that exogenous bilirubin can protect against hypoxia induced injury in cultured cells and in isolated perfused hearts subjected to I/R injury [15][16][17]. Furthermore, a strong correlation has been reported between elevated plasma bilirubin levels and lower risk of cardiovascular diseases [18,19].…”